RARE Daily

Advancing a Gene Therapy for a Rare and Fatal CNS Disorder

March 30, 2023

GM1 gangliosidosis is a rare and deadly lysosomal storage disorder that causes progressive damage to neurons in the brain, as well as the heart, liver, bones and other tissues throughout the body. There are currently no approved therapies to treat the condition. Passage Bio, which has a collaboration with the Gene Therapy Program at the University of Pennsylvania, is developing a gene therapy to the condition. We spoke to Samiah Al-Zaidy, vice president of clinical development for Passage, about GM1 gangliosidosis, the company’s experimental therapy to treat the condition, and what’s known about the therapy from work that’s been done to date.


Daniel Levine: Samiah, thanks for joining us.

Samiah Al Zaidy: Danny, thank you for having us.

Daniel Levine: We’re going to talk about Passage Bio, gene therapies, and your efforts to develop a treatment for the rare lysosomal storage disorder, GM1 gangliosidosis. I’d like to start with Passage Bio itself and the relationship with the Gene Therapy Program at the University of Pennsylvania on which it was founded in 2019. My guess is this was seen as a way to solve the translational research problem for the Penn Gene Therapy program while creating a reliable stream of preclinical candidates for Passage Bio, essentially outsourcing discovery. How has the relationship worked out in practice and what’s the interplay between the two organizations?

Samiah Al Zaidy: Excellent question. I will say that that is one of the highlights. I think working at Passage Bio is this amazing opportunity to have the partnership with the University of Pennsylvania Gene Therapy Program team. There’s tremendous talent on both sides, robust science from the Gene Therapy Program group, and we’ve got tremendous talent at Passage Bio to bring this to the clinic and advance these programs in clinical trials. Collaboration is ongoing and we’re very pleased with the partnership.

Daniel Levine: Well, let’s talk about GM1 gangliosidosis. What is this?

Samiah Al Zaidy: GM1 gangliosidosis is what we call an autosomal recessive genetic disease, which means it requires both parents for the most part to carry at least one copy of the defective gene where the patient who has GM1 gangliosidosis, in our case the children, will inherit one defective copy from each parent and then be affected with the disease. It is what we call a neuropathic lysosomal storage disease, and that basically implies that it does have neurological manifestations, but it is a result of an enzyme that is deficient or absent, called the beta galactosidase enzyme. And as a result of the deficiency or absence of the enzyme activity, there’s a buildup of toxic substrate in small organelles called the lysosomes that normally would be cleared out by the enzyme. So, they build up and eventually cause damage and, over time, atrophy of the nerve cells.

Daniel Levine: Well, how does the condition manifest itself and progress?

Samiah Al Zaidy: Do you know that while GM1 gangliosidosis is one of the devastating diseases of the neurogenerative disorders, it is a spectrum. And on one end of the spectrum you do have the very severe form, which presents in early infancy in the first few months of life. And then on the other end of the spectrum you do have the adult onset. Across the spectrum, this disease does rob patients from the quality of lifeand just being able to carry out the daily activities of their living. In the patients that we target, the early infantile and late infantile, it is devastating in the sense that these children develop significant neurological symptoms, lose any previously acquired healthy developmental milestones, and eventually, mostly in the early infantile they succumb to their disease in the first two to three years of life.

Daniel Levine: What’s the prognosis for someone with the condition today and are there any treatment options that exist?

Samiah Al Zaidy: Yeah, great question. Unfortunately, GM1 gangliosidosis does not have an approved treatment, so there’s a huge unmet need there that we’re trying to tap into with PBGM01 and the Imagine-1 clinical trial. at the moment, the only opportunity or only option in terms of management is really supportive care. So, once these families, and when we’re speaking regarding the patients, the younger patients that we are targeting, families receive the diagnosis, are offered supportive care. There’s really no treatment that is approved that could alter the natural history of the disease and result in regaining milestones or halting the progression of the disease. And that’s really what we’re aiming for with PBGM01.

Daniel Levine: How are patients generally diagnosed today and at what age do they get diagnosed?

Samiah Al Zaidy: The diagnosis poses a huge challenge for our GM1 gangliosidosis patients. There is no newborn screening. So the only way that these children or patients are diagnosed is after they develop symptoms. In many patients, it takes months to actually get a final diagnosis, and it’s largely due to overlapping symptoms between GM1 gangliosidosis and other neurodegenerative disorders. There’s this diagnostic odyssey given that it is a rare disease. So, ultimately they get tested and they’re discovered to have low levels of the beta galactosidase enzyme or absent levels at the time of diagnosis that leads to genetic confirmation. There are a few patients that happen to have family history or siblings who were affected by the disease, and those are most likely to genetic confirmation of their diagnosis probably early in the course of the disease or prior to them developing symptoms.

Daniel Levine: Despite the rarity of the condition, there were actually three companies, including Passage that had therapies in development. One of these companies, SIO Gene Therapies, announced it was shutting down and it ended its licensing agreement with the University of Massachusetts for its GM1 gangliosidosis program. But how does having these other programs out there affect development decisions?

Samiah Al Zaidy: Great question. Passage Bio from the start has built a model in which patients are put first and we have remained focused on those core values of putting the patients first. I cannot comment on other companies, but I will share that at Passage we do remain focused on clinical execution of the study and remain steadfast on in advancing PBGM01 to the clinic.

Daniel Levine: Did you find yourself having to compete for patients to enroll in the study, or is there an ample number of patients available?

Samiah Al Zaidy: We have a number of sites across several countries at this point and we’re incredibly grateful for the patients, the families in our study, investigators who have advanced the enrollment, and we’ve had an opportunity to enroll patients at a pace that aligns with our protocol.

Daniel Levine: Well, tell us about your experimental gene therapy. What is it and how does it work?

Samiah Al Zaidy: PBGM01 is a form of gene therapy that utilizes a virus or a viral factor to deliver the human GLB1 transgene. the human GLB1 trans gene codes for the beta galactosidase enzyme. Now, AAV, or adeno-associated virus, is one of the most widely used viral factors in gene therapy, mostly monogenic disorders due to its excellent safety profile. So, the AAV capsid that is used in PBGM01, AAVhu68, packages the full length transgene of the human GLB1 gene that is defective in these children and it delivers it to the target cells. And here, obviously, we want to target the central nervous system.

Daniel Levine: Passage has taken a somewhat different approach to delivery of the gene therapy than some of the other therapies I’ve seen out there. What’s the approach that Passage is taking and why is it taking that route of administration?

Samiah Al Zaidy: Great question. There are different administration methods for AAV and in my experience, different delivery methods target different cells. We do believe that Passage Bio for the GM1 gangliosidosis patients, PBGM01, has a great opportunity for efficient transduction in broader distribution in the central nervous system with the intra-cisterna magna delivery method. The delivery through the intra-cisterna magna allows us to deliver PBGM01 into the cerebrospinal fluid, enhancing the opportunity for more efficient, faster transduction to the central nervous system in a broader distribution. It also allows us to circumvent the systemic toxicity that has been reported on and is observed with systemic or intravenous delivery of AAV. And when you’re delivering into the CNS, you largely require lower viral vector loads and lower doses than when you deliver through systemic circulation.

Daniel Levine: So, I’m certainly no expert on brain anatomy, but I take it the cisterna magna is at the lower portion of the back of the head, correct?

Samiah Al Zaidy: It’s at the base of the skull.

Daniel Levine: So, does that require that you bore a hole? Do you just inject injected directly?

Samiah Al Zaidy: We have trained proceduralists who provide the administration under CT guidance with the use of contrast as necessary. It’s an injection with a needle, a highly specialized needle that is used in clinical practice for other purposes and it’s very similar to a lumbar puncture, which is a routine procedure done in clinic. It’s just delivered at a much higher level at the level of the cisterna magna, just at the basic skull.

Daniel Levine: Passage has focused on viral vectors. What’s the case for using AAV particularly with a neurological condition?

Samiah Al Zaidy: I’m happy to speak to that. Given my experience with AAVs, one of the most widely used viral vectors in gene therapy, it has an excellent safety profile. It is not known to cause disease in humans that we know of. It allows us to package a full-length transgene for GM1 gangliosidosis in the form that we have done for PBGM01. And one of the highlights for PBGM01 is the AAVhu68 capsid that is utilized in PBGM01 is a variant of the AAV9 serotype. And what we do know is AAV9 has demonstrated [in] both preclinical and clinical studies to have really good what we describe as transduction uptake into the central nervous system, as well as excellent biodistribution. And this, of course, serves a great purpose for treating our patients with neurogenic disorders with rapid progression, if you can get in there and ensure efficient transduction uptake into the cells in rapid translation and production of, or expression of, the transgene.

Daniel Levine: At the end of February, Passage provided updated data on its Imagine-1 phase 1/2 study of PBGM01. I’m sorry, I’m going to say that again. At the end of February, Passage Bio provided updated data on its Imagine-1 phase 1/2 study the gene therapy. What did the data show and what’s known about its safety and efficacy from what’s been done to date?

Samiah Al Zaidy: You’re correct, Danny. We at Passage Bio had a great opportunity at World 2023 to share an update on the safety and efficacy data for the first six patients in the Imagine-1 study. From a safety standpoint, we’re very encouraged by how well tolerated PBGM01 has been. We have had no treatment related serious adverse events. we have not seen peripheral neuropathy or dorsal root ganglion toxicity that’s been a concern in preclinical studies with AAV. And we have a favorable immune profile with new antibodies to the transgene product that we have seen. Now, what’s new at World 2023 that we shared in the end of February is what we’re really excited about. We’re building on what we previously shared in December of 2022. We continue to see meaningful improvement across the developmental areas for most of our patients who are milder at baseline. And we’re excited to share new data from a clinical standpoint as we’re encouraged by our MRI findings. So, this year we shared our MRI severity scores. The severity score is a score that was developed mostly in late infantile patients with GM1 gangliosidosis and juvenile patients. And it’s based on cerebral and cerebellar atrophy, but also white matter signal abnormalities and changes in some of the structures in the brain, including the basal ganglia and hippocampi. All of these regions in the brain are typically impacted in GM1 gangliosidosis. So, this score gives you an idea of how advanced the disease is and whether there is stabilization or changes. And what we’re really pleased to see is that although in the natural history, the higher the score, the more structural damage, what we’re seeing in our patients to date is that there’s stabilization of these scores over time. And we look forward to continuing to see how these children do and will continue to follow these outcomes. Also new at World and this year is we were pleased to share additional GM1 gangliosidosis substrate data. And we had previously shared in December biomarker data that showed a dose dependent response in our higher dose cohorts in the CSF beta galactosidase days activity as well as a dose dependent reduction in one of our GM1 gangliosides in the cerebral spinal fluid at the higher dose. So, we were really pleased to share new data on GM1 substrates, specifically the urine DP5 levels where we’re seeing a prominent reduction at the high dose. And this really just further supports our previous findings that suggest peripheral beta-gal enzyme activity. So collectively, we’re really excited to build on what we shared back in December in terms of a dose dependent response.

Daniel Levine: I know it’s early days. Is there anything that’s known about the durability of the therapy?

Samiah Al Zaidy: From experience I will share that proper assessment, as you just alluded to, of durability of treatment does indeed require time, especially in these neurogenerative disorders. All of our study participants are automatically rolled into a three year long-term follow-up study once they complete the first two years of the Imagine-1 study.

Daniel Levine: What’s the development path forward, and when do you think you might be in a position to seek approval?

Samiah Al Zaidy: At this stage of the study in the dose ascending phase, Passage Bio a remains focused on the clinical execution of the phase. And as we obtain additional data, this will inform the path forward.

Daniel Levine: Is the expectation that you would use a natural history study as a comparator?

Samiah Al Zaidy: That’s a great question, Danny, and I think, as in any open label study without a placebo arm, natural history data is critical. We have a key advantage through our partnership with the University of Pennsylvania. They’re conducting a natural history study. It continues to inform us in our development plan and it will continue to inform the path forward when it comes to our comparative group.

Daniel Levine: And is there any sense on how large a study might be necessary to seek approval?

Samiah Al Zaidy: Both studies are ongoing and we’ll continue to assess the totality of data from both studies and work with our collaborators to make such determinations.

Daniel Levine: This is a condition that is rapidly fatal. Is there any sense at how early patients will need to be treated to get the full benefit of a gene therapy?

Samiah Al Zaidy: You’re absolutely correct, Danny. And in my experience as a child neurologist and in this field with these devastating diseases, generally the earlier you can treat, the better the outcome. Now this will obviously vary from one disease to another, but we have previously shared how baseline developmental age appears to contribute to our treatment response. As a result, we are assessing modifications to our eligibility criteria to incorporate learnings from this observation and we’re looking forward to optimizing the risk benefit profile of PBGM01.

Daniel Levine: Samiah Al Zidy, vice president of Clinical Development for Passage Bio. Samiah, thanks so much for your time today.

Samiah Al Zaidy: Danny, it was my pleasure. Thank you for having me.

This transcript has been edited for clarity and readability.


Stay Connected

Sign up for updates straight to your inbox.